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Review
. 2015 Nov 1;4(11):631-640.
doi: 10.1089/wound.2014.0559.

Chemokine Regulation of Neutrophil Infiltration of Skin Wounds

Yingjun Su  1 , Ann Richmond  2
Affiliations
Review

Chemokine Regulation of Neutrophil Infiltration of Skin Wounds

Yingjun Su et al. Adv Wound Care (New Rochelle). .

Abstract

Significance: Efficient recruitment of neutrophils to an injured skin lesion is an important innate immune response for wound repair. Defects in neutrophil recruitment lead to impaired wound healing. Recent Advances: Chemokines and chemokine receptors are known to regulate neutrophil recruitment. Recent research advances reveal more mechanistic details about the regulation of chemokines and chemokine receptors on neutrophil egress from bone marrow, transmigration into the wound site, spatial navigation toward the necrotic skin tissue, and apoptosis-induced clearance by efferocytosis. Critical Issues: Skin injury triggers local and systemic alterations in the expression of multiple chemotactic molecules and the magnitude of chemokine receptor-mediated signaling. The responses of a number of CXC and CX3C chemokines and their receptors closely associate with the temporal and spatial recruitment of neutrophils to wound sites during the inflammatory phase and promote the clearance of necrotic neutrophils during the transition into the proliferative phase. Functional aberrancy in these chemokines and chemokine receptor systems is recognized as one of the important mechanisms underlying the pathology of impaired wound healing. Future Directions: Future research should aim to investigate the therapeutic modulation of neutrophil activity through the targeting of specific chemokines or chemokine receptors in the early inflammatory phase to improve clinical management of wound healing.

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Figures

None
Ann Richmond, PhD
<b>Figure 1.</b>
Figure 1.
Classification of chemokines and chemokine receptors. Most chemokines interact with multiple receptors, and a single receptor can interact with multiple chemokines. This is the case for most CC and CXC chemokines. Decoy receptors can also bind multiple chemokines. By contrast, a minority of receptors has only one ligand (refer to Bachelerie et al.).
<b>Figure 2.</b>
Figure 2.
Schematic illustration of the regulation of neutrophil recruitment into cutaneous wounds by both topical and systemic elements. Chemokine gradients are formed by secretions from platelets, monocytes, existing neutrophils, and resident cells in skin wound tissues shortly after injury. Circulating neutrophils transmigrate through venules and then follow a chemokine gradient to the site of the wound surface. Simultaneously, G-CSF (granulocyte colony-stimulating factor) and CXC-chemokines are released and delivered by blood circulation to bone marrow, leading to an imbalance between CXCR4- and CXCR2-mediated actions. Consequently, more matured bone marrow neutrophils egress into the peripheral pool and make their way to wound sites. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound
<b>Figure 3.</b>
Figure 3.
Multistep intravascular trafficking of neutrophils toward the site of injury. Necrotic cells induce spatially distinct chemoattractant gradient zones around the center of necrotic foci in the wound bed. When entering the wound adjacent area, neutrophils traffic at first by CXCR2-mediated chemotaxis along the endothelium lumen following intravascular chemokine gradients. Afterward, formyl-peptide receptor-dependent signaling dominates and neutrophils migrate into sites of necrosis by necrotaxis through a formyl-peptide gradient. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound
<b>Figure 4.</b>
Figure 4.
Chemokine receptor CXCR2 plays important roles for cutaneous wound healing. Ligand binding-induced CXCR2 signaling is required for normal recruitment of neutrophils and macrophages and for neovascularization and wound reepithelialization (A). In CXCR2−/− mice (B), the lack of CXCR2-mediated signaling leads to delayed neutrophil and macrophage recruitment into wound tissues, compromised angiogenesis, and significantly delayed reepithelialization. β-arrestin2 (βarr2) binds to the G-protein–coupled receptor kinase phosphorylated C-terminus of CXCR2 and functions as a regulator for CXCR2 signaling. In comparison to normal CXCR2 signaling during wound healing (C), knockout of βarr2 impedes receptor internalization so that CXCR2 receptors are detained in the cell membrane, leading to enhanced CXCR2-mediated signaling. As a result, neutrophil recruitment, wound tissue vessel density, and reepithelialization are significantly improved (D). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound
<b>Figure 5.</b>
Figure 5.
CXCR2/CXCR4 ligands antagonistically regulate neutrophil egress from bone marrow to peripheral pool. (A) Under physiological conditions, CXCR2 ligands CXCL1 and CXCL2 are constitutively expressed mainly by endothelial cells, while the CXCR4 ligand CXCL12 is largely expressed by osteoblasts in the bone marrow. Although bone marrow neutrophils express both CXCR2 and CXCR4, the CXCL12/CXCR4 interaction dominates, resulting in retention of most neutrophils within bone marrow through augmented binding of VLA-4 on neutrophils to VCAM-1 on bone marrow endothelial and stromal cells. During the maturation in bone marrow, the expression of neutrophil CXCR4 and VLA-4 are downregulated, resulting in a switch of dominant signaling from CXCR4 to CXCR2 that promotes egress of neutrophils into the peripheral pool. (B) Under pathological conditions, injury and infection stimulate production of CXCR2 ligands and G-CSF. G-CSF decreases the osteoblast numbers leading to reduction of CXCL12 expression, while simultaneously upregulating the expression of CXCR2 ligands. In addition, G-CSF prioritizes the switch of hematopoiesis toward myeloid lineages through the G-CSF-STAT3 axis. As a result, more mature neutrophils are developed and released into peripheral circulation. STAT3, signal transducer and activator of transcription 3; VCAM-1, vascular cell adhesion molecule 1; VLA-4, α4 integrin very later antigen. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound
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